Remedy for psychoneurotic diseases

ABSTRACT

A medicinal preparation for preventing and/or treating psychoneurotic diseases such as integration dysfunction and Alzheimer&#39;s disease which contains tropisetron or its pharmaceutically acceptable salt as the active ingredient.

RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. §371 of PCTInternational application PCT/JP2005/008123, filed Apr. 28, 2005.

TECHNICAL FIELD

The invention relates to a medicament for preventing and/or treatingpsychoneurotic disorders. More specifically, the invention relates to anagent for psychoneurotic disorders, containing tropisetron((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl1H-indole-3-carboxylate) or its pharmaceutically acceptable salt.

BACKGROUND ART

Accompanying with changes in social lifestyle and aging of society, theoverall number of patients with psychoneurotic disorders tends toincrease. For example, at present the number of patients withAlzheimer's disease, which is known as a representativeneurodegenerative disease, is estimated to be 1.5 million in Japan and4.0 million in the U.S. According to a prediction, this number increaseswith an increase in aged people in countries centering around developedcountries, and in 25 years, approximately 22 million people throughoutthe world will suffer from this disease. Currently, in the cognitivedysfunction of Alzheimer's disease (so-called dementia), the involvementof dysfunction of the acetylcholinergic nervous system in the brain hasbeen clarified on the basis of many neuropathological findings, andtherefore an inhibitor of acetylcholine degrading enzyme (cholinesteraseinhibitor) is clinically used. However, it is hard to say that theinhibitor is sufficiently therapeutically effective. Practically, thereis almost no effective method for the prevention and treatment of thedisease.

On the other hand, schizophrenia occurs in approximately 1% of thepopulation regardless of race and geographic area, and this is apsychoneurotic disorder, the onset of which often occurs in younggenerations from adolescence to the age of 20-29. The number of hospitalpatients with schizophrenia in Japan accounts for approximately 15% ofthe total number of hospital beds, resulting in a significant problem interms of medical cost. As symptoms of schizophrenia, there are positivesymptoms such as hallucination and delusion, negative symptoms such asflat or blunted emotion, lack of motivation and social withdrawal, aswell as cognitive dysfunction. Among these symptoms, cognitivedysfunction may possibly be a core symptom of schizophrenia, and isconsidered to deteriorate the quality of life (QOL) of patients.Pharmacological therapy is essential for the treatment of schizophrenia,and pharmaceutical agents such as phenothiazine compounds, butyrophenonecompounds, benzamide compounds, iminodibenzyl compounds, thiepinecompounds, indole compounds and serotonin-dopamine receptor blockers areadministered. However, although these pharmaceutical agents actuallyused in clinical sites are effective for positive symptoms such ashallucination and delusion, they show almost no effect on cognitivedysfunction. Thus, the development of therapeutic agents for cognitivedysfunction has been awaited in Japan and abroad.

Meanwhile, acetylcholine is one of the major neurotransmitters of thecentral nervous system, and is known to play an important role in theregulation of nervous activities in the cerebral cortex and hippocampus.In recent years, it is speculated that α7 subtype of nicotinic receptor(α7 nicotinic receptor) is involved in the pathological conditions ofpsychoneurotic diseases such as schizophrenia and Alzheimer's disease.

For example, in the brain (cerebral cortex and hippocampus, etc.) of aschizophrenic patient at autopsy, a decrease in the number of α7nicotinic receptors has been reported. It is also reported that anabnormality in P50 auditory evoked potential observed in schizophrenicpatients is improved by the administration of nicotine, and that α7nicotinic receptors are involved in this phenomenon (refer to Non-patentdocuments 1-6).

Similarly, in the cerebral cortex and hippocampus of patients withAlzheimer's disease at autopsy, a decrease in the number of nicotinicreceptors (α4β2 nicotinic receptors and α7 nicotinic receptors) has beenreported (refer to Non-patent documents 7-9). In addition, it isreported that the amount of α7 nicotinic receptor mRNA of thelymphocytes in Alzheimer's patients is significantly higher than that innormal subjects (refer to Non-patent document 10). It is also reportedthat the amount of α7 nicotinic receptor mRNA in the hippocampus ofAlzheimer's patients is significantly higher than that in normalsubjects (refer to Non-patent document 11). In this report, nodifference in the amount of mRNA in other subtypes (α3 and α4) wasobserved between the brain of Alzheimer's patients and the brain ofnormal subjects, suggesting that α7 nicotinic receptors play animportant role in the pathological condition of Alzheimer's disease(refer to Non-patent document 12).

As described above, α7 nicotinic receptors in the brain have beenspeculated to play an important role in psychoneurotic disorders such asschizophrenia and Alzheimer's disease. However, although severalcompounds including tropisetron and GTS-21 which affect α7 nicotinicreceptors are known at present (refer to Non-patent document 13), nopharmaceutical agent that has improving effects on these psychoneuroticdisorders, and also has pharmacokinetic features of resistance toadministration to humans as well as safety, has been reported; inaddition, in the above-mentioned non-patent document 13, no specificaction of tropisetron on psychoneurotic disorders such as schizophreniaand Alzheimer's disease, in particular on cognitive dysfunction, hasbeen described. Furthermore, with respect to tropisetron, this isoriginally used as an antiemetic agent having an antagonistic actionagainst serotonin 5-HT₃ receptor, and this kind of pharmaceutical agentis not known to be used for the prevention and treatment ofpsychoneurotic disorders. Thus, a pharmaceutical agent effective tohumans to such an extent that it can be actually used for the preventionand treatment of psychoneurotic disorders such as schizophrenia andAlzheimer's disease, and in particular psychoneurotic disorders withcognitive dysfunction, has not yet been known to date.

-   [Non-patent document 1] Freedman R, Adler L E, Bickford P, Byerley    W, Coon H, Cullum C M, Griffith J M, Harris J G, Leonard S, Miller    C, et al. Schizophrenia and nicotinic receptors. Harvard Reviews of    Psychiatry, 2:179-192, 1994.-   [Non-patent document 2] Leonard S, Adams C, Breese C R, Adler L E,    Bickford P, Byerley W, Coon H, Griffith J M, Miller C, Myles-Worsley    M, Nagamoto H T, Rollins Y, Stevens K E, Waldo M, Freedman R.    Nicotinic receptor function in schizophrenia. Schizophrenia    Bulletin, 22:431-445, 1996.-   [Non-patent document 3] Adler L E, Olincy A, Waldo M, Harris J G,    Griffith J, Stevens K, Flach K, Nagamoto H, Bickford P, Leonard S,    Freedman R. Schizophrenia, sensory gating, and nicotinic receptors.    Schizophrenia Bulletin, 24:189-202, 1998.-   [Non-patent document 4] Jones S, Sudweeks S, Yakel J L. Nicotinic    receptors in the brain: correlating physiology with function. Trends    in Neurosciences, 22:555-561, 1999.-   [Non-patent document 5] Freedman R, Adams C E, Leonard S. The    alpha7-nicotinic acetylcholine receptor and the pathology of    hippocampal interneurons in schizophrenia. J Chem Neuroanat 20:    299-306, 2000.-   [Non-patent document 6] NeuroReport, 10:1779-1782, 1999.-   [Non-patent document 7] Journal of Neurochemistry, 46:288-293, 1986.-   [Non-patent document 8] Alzheimer's Disease Reviews, 3:20-27, 1998.-   [Non-patent document 9] Alzheimer's Disease Reviews, 3:28-34, 1998.-   [Non-patent document 10] Alzheimer's Research, 3:29-36, 1997-   [Non-patent document 11] Molecular Brain Research, 66:94-103, 1999.-   [Non-patent document 12] Review: Japanese Journal of    Neuropsychopharmacology 22: 49-53, 2002.-   [Non-patent document 13] Macor J. E. et al., Bioorganic & Medicinal    Chemistry Letters, 11, 319-321, 2001.

DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention

Therefore, the development of preventive drugs and therapeutic drugs forpsychoneurotic disorders such as schizophrenia and Alzheimer's disease,in particular for cognitive dysfunction, has been desired. The object ofthe present invention is to provide a medicinal preparation effectivefor such psychoneurotic disorders.

Means of Solving the Problem

Inventors of the invention devoted themselves to the research to solvethe above problem, and found for the first time that an abnormality inP50 auditory evoked potential, which is one of the parameters ofcognitive dysfunction, observed in schizophrenic patients is improved bythe administration of tropisetron((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl1H-indole-3-carboxylate) that has an antagonistic action againstserotonin 5-HT₃ receptor and a partial agonistic action on α7 nicotinicreceptor, and completed this invention.

Namely, the invention relates to an agent for psychoneurotic disorders,containing tropisetron or its pharmaceutically acceptable salt.

The invention also relates to said agent for psychoneurotic disorders,wherein the psychoneurotic disorder is a psychoneurotic disorderassociated with acetylcholinergic nerves.

The invention also relates to the above agent for psychoneuroticdisorders, wherein the psychoneurotic disorder is a psychoneuroticdisorder which exhibits one or more of symptoms selected from the groupconsisting of cognitive dysfunction, attentional deficit disorder,depression, anxiety, epilepsy and pain.

The invention also relates to the above agent for psychoneuroticdisorders, wherein the psychoneurotic disorder is at least one of thedisorders selected from the group consisting of schizophrenia,Alzheimer's disease, Parkinson's disease, Huntington's disease andTourette's syndrome.

The invention also relates to the above agent for psychoneuroticdisorders, wherein the agent is used for the treatment of cognitivedysfunction in schizophrenia.

Effects of the Invention

Since tropisetron or its pharmaceutically acceptable salt inducesactivation of acetylcholinergic nerves in the brain due to itsantagonistic action against serotonin 5-HT₃ receptor and stimulatoryaction on α7 nicotinic receptor, an agent for psychoneurotic disordersof the invention containing tropisetron or its pharmaceuticallyacceptable salt exhibits effects on various psychoneurotic disorders,and is effective for their prevention and/or treatment. For example, theagent is effective in the prevention and/or treatment of psychoneuroticdisorders involving abnormalities in acetylcholinergic nerves,specifically, such as schizophrenia, Alzheimer's disease, Tourette'ssyndrome, Parkinson's disease, Huntington's disease as well as variouspsychoneurotic disorders exhibiting symptoms such as cognitivedysfunction, attentional deficit disorder, anxiety, depression, epilepsyand pain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows effects of tropisetron on abnormalities in P50 auditoryevoked potential observed in schizophrenic patients.

BEST EMBODIMENTS FOR CARRYING OUT THE INVENTION

First, meaning or definition of terms used herein is described. In thepresent invention, psychoneurotic disorders refer to a conceptencompassing various psychiatric disorders such as schizophrenia anddepression, various neurodegenerative disorders such as Alzheimer'sdisease, Parkinson's disease and Huntington's disease, and neurologicaldisorders such as Tourette's syndrome.

In the present invention, schizophrenia refers to a chronic neurologicaldisorder, the onset of which occurs mainly in early and middleadolescence, which has root symptoms of disturbance of ego and thinkingdisorder, and which progresses gradually while repeating positivesymptoms such as hallucination and delusion. In the present invention,Alzheimer's disease refers to a chronic neurodegenerative disorder, theonset of which occurs generally at the age of 60 or older, which iscalled senile dementia, and which progresses gradually with a centralsymptom of cognitive dysfunction.

The agent for psychoneurotic disorders containing tropisetron or itspharmaceutically acceptable salt of the invention can be administeredorally or parenterally. For oral administration, well-known forms ofadministration such as tablets, capsules, coated tablets, lozenges, andliquid preparations including solutions and suspensions can be used. Forparenteral administration, rectal administration using suppositories,transdermal administration using patches, liniments and gel,transmucosal administration using sprays and aerosols may be performed,and the administration may also be performed by intravenous,intramuscular, subcutaneous or intraventricular injection.

In the agent for psychoneurotic disorders of the invention, tropisetroncan be used as both forms of free base and its pharmaceuticallyacceptable salt. As pharmaceutically acceptable salts, pharmaceuticallyacceptable acid addition salts are preferred, and in particular,hydrochloride salt is preferred.

The agent for psychoneurotic disorders of the invention can containother medicinal components in addition to tropisetron or itspharmaceutically acceptable salt. Furthermore, in addition to thesemedicinal components, physiologically-acceptable appropriate substanceswell known to those skilled in the art can be contained, which include,without limitation, antioxidants, stabilizers, preservatives, flavoringagents, coloring agents, solubilizing agents, solubilizers, surfactants,emulsifiers, antifoaming agents, viscosity modifiers, gelatinizingagents, absorption promoters, dispersants, excipients, pH modifiers andothers.

Thus, the agent for psychoneurotic disorders of the invention can beprepared by appropriately blending tropisetron or its pharmaceuticallyacceptable salt with the above-mentioned substances. When the agent forpsychoneurotic disorders of the invention is prepared as an injectionpreparation (for subcutaneous, intramuscular, or intravenous injection),a form of solution or suspension is particularly preferred; when it isprepared for vaginal or rectal administration, a form of semi-solidagent such as creams or suppositories is particularly preferred; when itis prepared for transnasal administration, a form of powder, nose drop,or aerosol is particularly preferred. Any of these preparations can beprepared in accordance with any method of pharmaceutical technologywell-known to those skilled in the art, such as those described inRemington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.,1970). In the injection preparations, for example, blood-plasma-derivedproteins such as albumin, amino acids such as glycine, and sugars suchas mannitol can be added; in addition, buffering agents, solubilizingagents, isotonic agents and others can be added. For use as aqueouspreparations or lyophilized agents, preferably a surfactant such asTween® 80 or Tween® 20 is added to prevent coagulation. Parenteralformulations other than injection preparations may contain distilledwater or saline, polyalkylene glycol such as polyethylene glycol,vegetable derived oil, hydrogenated naphthalene and others. Preparationsfor vaginal or rectal administration such as suppositories contain, forexample, polyalkylene glycol, petroleum jelly, cacao oil, etc., as ageneral excipient. Preparations for vaginal administration may containabsorption promoters such as bile salt, ethylenediamine salt, citrateand others. Preparations for inhalation may be a solid, and may contain,for example lactose as an excipient; preparations for nose drop may bewater or oily solution.

The accurate dose and regimen of the agent for psychoneurotic disordersof the invention are adjusted depending on factors such as the amountrequired, therapeutic method, type of disease and degree of necessity ofeach subject to be treated. Specifically, the dose can be determineddepending on the age, body weight, general state of health, sex, diet,the time and route of administration, excretion rate, combination ofpharmaceutical agent, and disease state of a patient; other factors canbe taken into consideration as well. Tropisetron or its pharmaceuticallyacceptable salt does not show pharmacokinetic problems in humans, andcan be used safely. Its daily dose differs depending on the state andbody weight of a patient, the kind of compound and the administrationroute. However, it is desirable that for parenteral administration, theagent is administered subcutaneously, intravenously, intramuscularly orrectally at a dose of approximately 0.01-100 mg/person/day as atropisetron (free base), preferably at 0.1-50 mg/person/day; and fororal administration, the agent is administered at a dose ofapproximately 0.01-500 mg/person/day, preferably at 0.1-100mg/person/day.

EXAMPLES

The invention is described more specifically with reference to examplesbelow, but the invention should not be limited to these examples. Inaddition, various modifications can be made within the range of thetechnical idea of the invention.

Example 1

(1) Subject

Twenty-two patients with schizophrenia (14 males and 8 females, averageage: 39.8 years old (standard deviation 14.0), age range: 18-60 yearsold) were selected as subjects. The subjects were diagnosed bypsychiatrists on the basis of DSM-IV criteria. Psychiatric symptoms andcognitive functions of the subjects were evaluated using BriefPsychiatric Rating Scale (BPRS), Global Assessment of Functioning (GAF),Mini-Mental State Examination (MMSE) and Wechsler Adult IntelligenceScale-Revised (WAIS-R).

(2) Experimental Method

First, a baseline P50 auditory evoked potential of a subject wasmeasured (conditioning P50), then the P50 was measured 1 h afteradministration of 10 mg of tropisetron (test P50). P50 is a positivebrain wave which appears approximately 50 m seconds after an auditorystimulus. Consecutive click sounds with an interval of 500 m seconds(conditioning stimulus and test stimulus) at 70 dB were presented every10 seconds for 120 times, and the brain wave measured at the parietalregion was summed to identify P50. The resistance of an electrode wasset at 10 kW or less, and the brain wave exceeding ±70 mV was omitted asartifact. The largest positive wave between 40 ms and 90 ms after theconditioning stimulus was designated to be the conditioning P50, and thepositive wave after the test stimulus whose latency is the closest tothat of the conditioning P50 was designated to be the test P50. Theamplitude of P50 was defined as the difference between the positive peakand the preceding negative trough. The P50 ratio was defined as theamplitude of the test P50 divided by the amplitude of the conditioningP50.

(3) Statistical Analysis

Data were expressed as average±standard deviation. The statisticalanalysis between two groups was performed using Student's t-test. Therelationship between variables was confirmed by Pearson's product-momentcorrelation coefficient. p Values of 0.05 or less were designated to bestatistically significant.

(4) Results

Results of the baseline P50 from 22 subjects were analyzed. Theamplitudes of the conditioning P50 and test P50 were 2.59±1.45 and1.76±1.00, respectively, and their latencies were 59.64±13.03 and57.18±16.15, respectively. The P50 ratio was 0.84±0.55. The baseline P50ratios of three subjects (13.6%) were 0.5 or less (0.07, 0.25, 0.28).Table 1 shows average values of data from 19 subjects in whom baselineP50 ratio was larger than 0.5. While no significant differences in boththe amplitude and latency of conditioning P50 were observed betweenbefore and after the administration of tropisetron (t=0.79, df=18,p=0.44; t=1.05, df=18, p=0.31), there was a significant decrease in theP50 ratio between before and after the administration of tropisetron(t=2.32, df=18, p=0.033). FIG. 1 shows P50 ratios before and after theadministration of tropisetron in 19 subjects. In four subjects, the P50ratio improved to 0.5 or less.

As shown in the above results, P50 ratios significantly decreased by theadministration of tropisetron in patients with schizophrenia and thus itis understood that tropisetron improves cognitive dysfunction inschizophrenia. Accordingly, the agent for psychoneurotic disorderscontaining tropisetron or its pharmaceutically acceptable salt was shownto be effective as a preventive drug and/or therapeutic drug forpsychoneurotic disorders including schizophrenia and those exhibitingcognitive dysfunction.

TABLE 1 Effects of tropisetron on abnormalities in P50 auditory evokedpotential in schizophrenic patients. Before After P50 CharacteristicMean SD Mean SD Amplitute (mV) conditioning 2.40 1.31 2.65 1.47 test1.93 0.96 1.45 1.24 Latency (msec) conditioning 58.21 12.61 59.79 13.41test 55.79 15.98 59.16 14.02 P50(T/C)ratio 0.94 0.53 0.61* 0.33*Significant between-group difference (t = 2.32, df = 18, p = 0.032)

INDUSTRIAL APPLICABILITY

As explained above, the agent for psychoneurotic disorders of theinvention can be used as an effective medicament for variouspsychoneurotic disorders including schizophrenia and Alzheimer'sdisease, in particular cognitive dysfunction for which no effectivepharmaceutical agents exist to date.

The invention claimed is:
 1. A method for treating abnormality in P50 auditory evoked potential of cognitive dysfunction in schizophrenia, comprising: (a) measuring a baseline P50 auditory evoked potential ratio of a subject, (b) administering to the subject whose baseline P50 auditory evoked potential ratio is larger than 0.5 an agent containing tropisetron or its pharmaceutically acceptable salt at a dose of tropeistron free base of at least 10 mg/day, and (c) measuring P50 auditory evoked potential ratio of the subject, wherein it is determined that the cognitive dysfunction is improved if the P50 auditory evoked potential ratio is 0.5 or less.
 2. The method according to claim 1, wherein the agent containing tropisetron or its pharmaceutically acceptable salt is administered orally at a dose of tropisetron free base of 10-500 mg/day.
 3. The method according to claim 2, wherein the agent containing tropisetron or its pharmaceutically acceptable salt is administered orally at a dose of tropisetron free base of 10-500 mg/day.
 4. The method according to claim 3, wherein the agent containing tropisetron or its pharmaceutically acceptable salt is administered orally at a dose of tropisetron free base of 10 mg/day. 